Experimental allergic encephalomyelitis (EAE), an inflammatory disease of the central nervous system (CNS), is used as an animal model for human multiple sclerosis (MS). Demyelination and cell infiltration within the CNS are characteristic features associated with both EAE and MS. The involvement of the immune system in these diseases is beyond doubt and both EAE and MS are viewed as autoimmune diseases. Myelin-specific T lymphocytes display an increased frequency in MS patients and their animal counterparts transfer EAE into naive mice or rats. The implication of T lymphocytes in this form of CNS disease is well accepted and approaches targeting modulation of these aggressive cells are being considered as strategies to suppress the disease. Administration of antigen into animals without adjuvant induces inactivation rather than priming of immune responses. The absence of adjuvant leads to a lack of the inflammatory stimuli required for up-regulation of costimulatory molecules on antigen presenting cells (APCs). Under these circumstances, presentation will be carried out by APCs expressing minimal costimulatory molecules leading rather to tolerization of T cells. Self-peptides free of adjuvant have been used for modulation of autoreactive T cells and success has been met in animals. However, in humans repetitive injections were required leading to allergic reactions and in some cases premature termination of clinical trials. Genetic insertion of self-peptides into the variable region of immunoglobulins (Igs) generates Ig-self-peptide chimeras that would be more resistant to degradation and vehicle the peptides into APCs via Fcgamma receptors (Fc(Rs). Within the APC, the self-peptide is cleaved from the chimera, and access newly synthesized major histocompatibility complex (MHC) molecules. Consequently, peptide delivery on Igs magnifies presentation compared to free peptide. Aggregation of Igs cross-links FcgammaRs on APCs and triggers the production of IL-10. Since Igs are autologous proteins they do not up-regulate the expression of costimulatory molecules on APCs when injected into animals in saline. Consequently, delivery of self-peptides by aggregated Igs will lead to effective presentation of self-peptides by APCs that would be producing IL-10 and lacking costimulatory molecules. We hypothesize that broad and effective suppression of diverse T cell specificities will be the outcome of this presentation. To test this hypothesis, we propose to engineer myelin peptides into Igs, and evaluate the resulting Ig-myelin chimeras for bystander suppression of diverse autoreactive T cells and therapy of forms of EAE resembling circumstances of human MS.